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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of the Safety and Tolerability of N–Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis with Background Treatment of Pirfenidone

    Summary
    EudraCT number
    		 2012-000564-14
    Trial protocol
    		 BE   SE   DE   IT   AT   GB   DK  
    Global end of trial date
    24 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Apr 2016
    First version publication date
    30 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PIPF-023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02707640
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of treatment with N-acetylcysteine (NAC) (1800 milligram/day [mg/day]) in subjects with mild to moderate idiopathic pulmonary fibrosis (IPF) with background treatment of pirfenidone therapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 Pirfenidone was an oral administration of a dose of at least 1602 mg/day and no more than 2404 mg/day during the wash-out and screening period and for at least 8 weeks prior to randomisation.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Italy: 20
    Worldwide total number of subjects
    122
    EEA total number of subjects
    122
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    40
    From 65 to 84 years
    82
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening details: A total of 123 subjects were enrolled. Total of 122 subjects received at least 1 dose of double-blind study medication, and thus included in the modified intent-to-treat (mITT) population

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 N–Acetylcysteine (NAC)
    Arm description
    		 Subjects randomised to this arm were administered NAC three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed until 4 weeks after last study treatment dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N–Acetylcysteine (NAC)
    Investigational medicinal product code
    Other name
    Fluimucil
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 600 mg NAC effervescent tablets orally three times a day.

    Arm title
    		 Placebo
    Arm description
    		 Subjects randomised to this arm were administered matching placebo orally three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed until 4 weeks after last study treatment dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo to NAC orally three times a day.

    Number of subjects in period 1
    		N–Acetylcysteine (NAC) Placebo
    Started
    60
    62
    Completed
    52
    55
    Not completed
    8
    7
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    -
    1
         Subject's personal decision
    1
    2
         Adverse event, non-fatal
    4
    2
         Sponsor discretion
    1
    -
         Principal investigator discretion
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    N–Acetylcysteine (NAC)
    Reporting group description
    		 Subjects randomised to this arm were administered NAC three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed until 4 weeks after last study treatment dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to this arm were administered matching placebo orally three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed until 4 weeks after last study treatment dose.

    Reporting group values
    		 N–Acetylcysteine (NAC) Placebo Total
    Number of subjects
    		 60 62 122
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.7 ( 7.99 ) 67.5 ( 6.22 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 11 18
        Male
    		 53 51 104

    End points

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    End points reporting groups
    Reporting group title
    N–Acetylcysteine (NAC)
    Reporting group description
    		 Subjects randomised to this arm were administered NAC three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed until 4 weeks after last study treatment dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to this arm were administered matching placebo orally three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed until 4 weeks after last study treatment dose.

    Primary: Percentage of Subjects With Dose Reductions

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    End point title
    		 Percentage of Subjects With Dose Reductions [1]
    End point description
    Percentage of subjects with dose reductions in N-Acetylcysteine and placebo cohorts during the 24-week treatment period. mITT population included subjects who received at least 1 dose of double-blind study medication (NAC or placebo).
    End point type
    Primary
    End point timeframe
    From baseline up to 24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    		 N–Acetylcysteine (NAC) Placebo
    Number of subjects analysed
    60
    62
    Units: percentage of subjects
        number (not applicable)
    5
    4.8
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Early Treatment Discontinuations

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    End point title
    		 Percentage of Subjects with Early Treatment Discontinuations [2]
    End point description
    Percentage of subjects with early study treatment discontinuations in N-Acetylcysteine and placebo cohorts during the 24-week treatment period. mITT population included subjects who received at least 1 dose of double-blind study medication (NAC or placebo).
    End point type
    Primary
    End point timeframe
    From baseline up to 24 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    		 N–Acetylcysteine (NAC) Placebo
    Number of subjects analysed
    60
    62
    Units: percentage of subjects
        number (not applicable)
    14.8
    11.3
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs) [3]
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a subject who is administered a study treatment regardless of whether or not the event has a causal relationship with the treatment. An AE, therefore, could be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the study treatment, whether or not related to the treatment. mITT Population included subjects who received at least 1 dose of double-blind study medication (NAC or placebo).
    End point type
    Primary
    End point timeframe
    Until 28 days from last dose of study treatment (Week 28)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    		 N–Acetylcysteine (NAC) Placebo
    Number of subjects analysed
    60
    62
    Units: percentage of subjects
        number (not applicable)
    76.7
    80.6
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-Emergent Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Serious Adverse Events (SAEs) [4]
    End point description
    A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in death, is life threatening, requires hospitalization or prolongation of hospitalization, or results in disability/incapacity, or congenital anomaly/birth defect. mITT population included subjects who received at least 1 dose of double-blind study medication (NAC or placebo).
    End point type
    Primary
    End point timeframe
    Until 28 days from last dose of study treatment (Week 28)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    		 N–Acetylcysteine (NAC) Placebo
    Number of subjects analysed
    60
    62
    Units: percentage of subjects
        number (not applicable)
    5
    6.5
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-Emergent Adverse Events Resulting in Permanent Discontinuation of Study Treatment

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events Resulting in Permanent Discontinuation of Study Treatment [5]
    End point description
    mITT population included subjects who received at least 1 dose of double-blind study medication (NAC or placebo).
    End point type
    Primary
    End point timeframe
    Until 28 days from last dose of study treatment (Week 28)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    		 N–Acetylcysteine (NAC) Placebo
    Number of subjects analysed
    60
    62
    Units: percentage of subjects
        number (not applicable)
    6.7
    1.6
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-Emergent Deaths of All Causes

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Deaths of All Causes [6]
    End point description
    mITT population included who received at least 1 dose of double-blind study medication (NAC or placebo).
    End point type
    Primary
    End point timeframe
    Until 28 days from last dose of study treatment (Week 28)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    		 N–Acetylcysteine (NAC) Placebo
    Number of subjects analysed
    60
    62
    Units: percentage of subjects
        number (not applicable)
    1.7
    4.8
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-Emergent Adverse Events That Led to Dose Reduction or Temporary Discontinuation of Study Treatment

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events That Led to Dose Reduction or Temporary Discontinuation of Study Treatment [7]
    End point description
    mITT population included who received at least 1 dose of double-blind study medication (NAC or placebo).
    End point type
    Primary
    End point timeframe
    Until 28 days from last dose of study treatment (Week 28)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    		 N–Acetylcysteine (NAC) Placebo
    Number of subjects analysed
    60
    62
    Units: percentage of subjects
        number (not applicable)
    10
    6.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until 28 days from last dose of study treatment (Week 28)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    N–Acetylcysteine (NAC)
    Reporting group description
    		 Subjects randomised to this arm were administered NAC three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed for 4 weeks after last study treatment dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to this arm were administered matching placebo orally three times daily and a dose of pirfenidone of at least 1602 mg/day for 24 weeks. Subjects were to be on a dose of pirfenidone of at least 1602 mg/day for a minimum of 8 weeks prior to randomisation and were followed for 4 weeks after last study treatment dose.

    Serious adverse events
    		 N–Acetylcysteine (NAC) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 62 (6.45%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 N–Acetylcysteine (NAC) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 60 (76.67%)
    50 / 62 (80.65%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 60 (1.67%)
    5 / 62 (8.06%)
         occurrences all number
    1
    5
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Diarrhoea
         subjects affected / exposed
    6 / 60 (10.00%)
    9 / 62 (14.52%)
         occurrences all number
    9
    10
    Nausea
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 62 (8.06%)
         occurrences all number
    4
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 60 (13.33%)
    7 / 62 (11.29%)
         occurrences all number
    8
    11
    Dyspnoea
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 62 (6.45%)
         occurrences all number
    3
    6
    Productive cough
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 62 (3.23%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Photosensitivity reaction
         subjects affected / exposed
    8 / 60 (13.33%)
    1 / 62 (1.61%)
         occurrences all number
    9
    1
    Rash
         subjects affected / exposed
    2 / 60 (3.33%)
    6 / 62 (9.68%)
         occurrences all number
    3
    6
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 62 (1.61%)
         occurrences all number
    4
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 62 (4.84%)
         occurrences all number
    4
    3
    Influenza
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 62 (1.61%)
         occurrences all number
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    7 / 60 (11.67%)
    7 / 62 (11.29%)
         occurrences all number
    7
    7
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 62 (8.06%)
         occurrences all number
    3
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2014
    Study sample size estimate was reduced from 125 subjects per arm to allow for an observed exposure of approximately 62.5 subject-years per arm to 60 subjects per arm for an observed exposure of approximately 30 subject-years per arm which was considered reasonably long to detect potential differences of the safety and tolerability of NAC added to background treatment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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